Pendant Alkoxy Groups on N-Aryl Substitutions Drive the Efficiency of Imidazolylidene Catalysts for Homoenolate Annulation from Enal and Aldehyde

Article abstract of DOI:10.1002/anie.202008631

Hydrogen-transfer in the tetrahedral intermediate generated from an imidazolylidene catalyst and α,β-unsaturated aldehyde forms a conjugated Breslow intermediate. This is a critical step affecting the efficiency of the NHC-catalyzed γ-butyrolactone formation via homoenolate addition to aryl aldehydes. A novel type of imidazolylidene catalyst with pendant alkoxy groups on the ortho-N-aryl groups is described. Catalyst of this sort facilitates the formation of the conjugated Breslow intermediate. Studies of the rate constants for homoenolate annulation affording γ-butyrolactones, reveal that introduction of the oxygen atoms in the appropriate position of the N-aryl substituents can increase the efficiency of imidazolylidene catalysts. Structural and mechanistic studies revealed that pendant alkoxy groups can be located close to the proton of the tetrahedral intermediate, thereby facilitating the proton transfer.

Full text of DOI:10.1002/anie.202008631

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Accepted Article
Title: Pendant Alkoxy Groups on N-Aryl Substitutions Drive the
Efficiency of Imidazolylidene Catalysts for Homoenolate
Annulation from Enal and Aldehyde
Authors: Ruji Kyan, Kohei Sato, Nobuyuki Mase, and Tetsuo Narumi
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Pendant Alkoxy Groups on N-Aryl Substitutions Drive the
Efficiency of Imidazolylidene Catalysts for Homoenolate
Annulation from Enal and Aldehyde
Ryuji Kyan[a], Kohei Sato[b,c], Nobuyuki Mase[a,b,c,d] and Tetsuo Narumi* [a,b,c,d]
Abstract: Hydrogen-transfer in the tetrahedral intermediate
generated from an imidazolylidene catalyst and ,-unsaturated
aldehyde forms a conjugated Breslow intermediate. This is a critical
step affecting the efficiency of the NHC-catalyzed -butyrolactone
formation via homoenolate addition to aryl aldehydes. A novel type
of imidazolylidene catalyst with pendant alkoxy groups on the ortho-
N-aryl groups is described. Catalyst of this sort facilitates the
formation of the conjugated Breslow intermediate. Studies of the rate
constants for homoenolate annulation affording -butyrolactones,
reveal that introduction of the oxygen atoms in the appropriate
position of the N-aryl substituents can increase the efficiency of
imidazolylidene catalysts. Structural and mechanistic studies
revealed that pendant alkoxy groups can be located close to the
proton of the tetrahedral intermediate, thereby facilitating the proton
transfer.
homoenolate equivalent (III) to the aryl aldehyde results in the
formation of an adduct (IV). This is followed by tautomerization
and cyclization to form a -butyrolactones. Using NHC-catalyzed
generation of homoenolate equivalents,3 a series of synthetic
methodologies producing multi-substituted heterocycles and
carbocycles including -lactams,4 cyclopentenes,5 -lactones,6
bicyclic -lactones7 or benzenes7 have been developed.
However, the further exploration of this rich chemistry is
currently hampered by the paucity of methods for increasing the
homoenolate reactivity of NHCs8 and by poor examples of the
mechanistic and the kinetic studies of homoenolate reactions
catalyzed by NHC, particularly imidazolylidenes9 and
imidazolinylidenes.10
Conjugated Breslow intermediates, generated by the
reaction of ,-unsaturated aldehydes with N-heterocyclic
carbenes (NHCs), are reactive species that enable conversion of
simple carbonyl compounds to structurally complex molecules.1
In particular, the umpolung activation of ,-unsaturated
aldehydes generates a homoenolate species with both a
nucleophilic site at the -carbon and an electrophilic site at the
carbonyl carbon. This species allows unique bond formations
that differ from the classical examples. Glorius and Bode
independently reported the first NHC-catalyzed homoenolate
reaction for -butyrolactone formation using imidazolium-derived
NHCs (imidazolylidenes).2 Mechanistically, reaction of the
imidazolylidenes with ,-unsaturated aldehydes generates the
tetrahedral intermediate (I), which can be converted by
hydrogen transfer to the conjugated Breslow intermediate (II)
(Scheme 1). Subsequently, nucleophilic attack by the
Scheme 1. NHC-catalyzed -butyrolactone formation via homoenolate addition.
The N-aryl groups of NHCs play a critical role in
determining the nature of NHC catalysts including the acidity of
the precatalysts,11 the reaction preference,12 and the kinetic
profiles.13 As part of our interest in the development of effective
NHC catalysts for the homoenolate-mediated reactions, we
recently reported the substituent effects of the N-aryl groups of
imidazolylidenes on their catalyst activity for homoenolate
annulation in the presence of excess base affording -
butyrolactones (Figure 1a).9 In that study, the 2,6-diethylphenyl
group was identified as a suitable N-aryl group and the
imidazolylidene with 2,6-diethylphenyl groups showed higher
catalyst activity than the frequently used IMes in the reaction.
Moreover, our mechanistic studies revealed that the effect of the
2,6-diethylphenyl groups could affect the hydrogen-transfer step
which limits the turnover.
[a]
R. Kyan, Prof. Dr. N. Mase, Dr. T. Narumi
Graduate School of Science and Technology, Shizuoka University
3-5-1 Johoku, Hamamatsu 432-8561 Shizuoka (Japan)
E-mail: narumi.tetsuo@shizuoka.ac.jp
[b]
[c]
Dr. K. Sato, Prof. Dr. N. Mase, Dr. T. Narumi
Department of Applied Chemistry and Biochemical Engineering,
Faculty of Engineering, Shizuoka University (Japan)
Dr. K. Sato, Prof. Dr. N. Mase, Dr. T. Narumi
Course of Applied Chemistry and Biochemical Engineering,
Department of Engineering, Graduate School of Integrated Science
and Technology, Shizuoka University (Japan)
[d]
Prof. Dr. N. Mase, Dr. T. Narumi
Research Institute of Green Science and Technology, Shizuoka
University (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202008631
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COMMUNICATION
Figure 1. Imidazolylidene catalysts for homoenolate annulation.
Scheme 2. Synthesis of imidazolium salts 4a-4h.
Based our observations concerning the potentials of N-aryl
groups as NHC catalysts, we considered the possibility of the
functionalization of N-aryl substituents that could promote the
formation of the conjugated Breslow intermediates (Figure 1b).
This led us to the catalyst design utilizing the proximity effects by
Lewis bases functionality that have been reported to increase
the rate of nucleophilic addition of NHC into the aryl aldehyde
substrates13c and also to accelerate the proton transfer in the
tetrahedral intermediates.13a
In this study, we describe the proximity effects on
tetrahedral intermediates in imidazolylidene catalysis with
pendant alkoxy groups. These studies reveal that introduction of
the oxygen atoms on the ortho-substituents of N-aryl groups of
the imidazolylidene catalysts leads to enhancement of the
efficiency of the imidazolylidene catalysts in -butyrolactone
formation. In particular, the imidazolylidene catalysts bearing 2-
methoxyethyl-6-methylphenyl groups show higher homoenolate
reactivity than IMes. Mechanistic studies disclosed that the
introduced oxygen functionalities can facilitate the hydrogen-
transfer of the tetrahedral intermediate in turnover-limiting steps,
resulting in acceleration of the generation of the conjugated
Breslow intermediate.
To examine this catalyst design, we evaluated the catalytic
activities of precatalysts 4b-4e with pendant alkoxy groups on N-
aryl ortho-substituents (Figure 2). As a standard condition, the
reaction of cinnamaldehyde (5, 1.0 equiv) with para-
bromobenzaldehyde (6, 2.0 equiv) was carried out in the
presence of 10 mol% of the imidazolium salt and 10 mol% of 7-
methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) in THF-d8
(0.5 M) at 25 °C in an NMR tube, and the conversion was
monitored by 1H NMR spectroscopy. In this reaction systems,
the conjugated Breslow intermediate is always present in
catalytic amounts, so the electrophile, benzaldehyde is
essentially in large excess. Thus, standard kinetic analysis of the
conversion of cinnamaldehyde (5) to -butyrolactone (7) exhibits
a
pseudo-first-order dependence as
a
function of
cinnamaldehyde concentration versus time over half-lives. The
observed rate constant of the reaction with IMes・HClO4 (4a)
was 2.95 × 10-2 min-1.9 The catalytic activity of the precatalyst
(4b) with 2-methoxy-6-methylphenyl groups was k4b = 0.41 × 10-
2 min-1, much lower than that of 4a. In contrast, the activity of
precatalyst (4c) with 2-methoxymethyl-6-methylphenyl (k4c =
2.67 × 10-2 min-1) groups was comparable to that of 4a (k4c/k4a =
0.91). The activity of the precatalyst (4d) with 2-methoxyethyl-6-
methylphenyl groups was higher than that of 4a (k4d = 4.12 × 10-
2 min-1; k4d/k4a = 1.40). We also examined the precatalyst (4e),
whose 2-(3-methoxypropyl)-6-methylphenyl groups contain
longer alkyl linkers. The activity of precatalyst (4e) was lower
than that of 4a (k4e = 2.24 × 10-2 min-1; k4e/k4a = 0.76).16
For the development of novel imidazolylidene catalysts
with pendant alkoxy groups, we synthesized a series of
imidazolium salts (Scheme 2) in 5-45% yield in 3 steps. Briefly,
the corresponding anilines (1) reacted with 40% glyoxal under
acidic conditions to give diimines (2). Subsequently, the diimines
(2) were converted to imidazolium chlorides (3).14 The pure
imidazolium salts were obtained after the anion exchange of the
chloride (3) to form the perchlorate (4).15
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10.1002/anie.202008631
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COMMUNICATION
O
O
O
O
O
O
10 mol % precatalyst
10 mol % MTBD
O
H
+
Ar
=
Ph
H
Br
6 (2.0 equiv)
C6H4-p-Br
THF-d8 (0.5 M)
4-tBuC6H4OMe
25 ºC in NMR
Me
Br
Ph
7
Me
Me
Me
5
-cis/trans
4c-Br
4c
4c-Me
k4c-Br = 0.78 × 10-2
k4c = 2.66 × 10-2
k4c-Me = 3.21 × 10-2
1.80
rate constant
k
1.60
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
IMes•HClO4 4a
0
1.0
2.0
3.0
4.0
5.0 × 10-2 [min]
4d
O
O
O
Ar
N
Ar
=
N
Me
Br
Ar
Me
Me
Me
ClO4
4d-Me
4d
4d-Br
4e
k4d-Me = 3.24 × 10-2 k4d = 4.12 × 10-2 k4d-Br = 4.51 × 10-2
4b
4c
Figure 3. Effect of para-substituents of N-aryl groups on the catalytic activities.
0
10
20
30
40
[min]
We conducted a competition experiment between ether-
linked precatalyst (4d) and the precatalyst (4h) bearing a
methylene linker (Scheme 3). Under the same conditions, the
ether-type precatalyst (4d) has higher catalytic activity than the
methylene-type precatalyst (4h) (k4h = 1.75 × 10-2 min-1),
demonstrating the significant effect in this reaction of the
pendant alkoxy groups.
Figure 2. Kinetic profiles of γ-butyrolactone formation with precatalysts 4a-4e.
To gain further information about the effect of the pendant
alkoxy groups, we investigated the position of the oxygen atom
without changing the length of the ortho-substituent using the
precatalysts 4d, 4f and 4g. This modification revealed that both
the length of the ortho-substituents and the position of the
oxygen atoms both contribute to the activity of the catalyst.17
Also, we examined the effect of para-substituents of the 2-
methoxy-methyl-6-methylphenyl (4c) and 2-methoxy-ethyl-6-
methylphenyl (4d) groups on the catalytic activity (Figure 3).
When the imidazolium salt (4c) containing 2-methoxy-methyl-6-
methylphenyl groups was employed, the electron-donating
methyl group proved to be a suitable para-substituent and the
methyl-substituted precatalyst (4c-Me) showed higher activity
than the precatalyst (4c). The catalytic activity of the precatalyst
(4c-Me) was 1.2-fold higher than that of 4c (k4c-Me = 3.21 × 10-2
min-1). On the other hand, the catalytic activity of para-bromo
substituted precatalyst (4c-Br) was lower than that of 4c (k4c-Br =
0.78 × 10-2 min-1). In contrast, imidazolium salts (4d) with 2-
methoxy-ethyl-6-methylphenyl groups showed a trend opposite
to that of the 2-methoxy-methyl-6-methylphenyl-type precatalyst
with respect to the para-substituents. Although the catalytic
activity of the para-methyl substituted precatalyst (4d-Me) was
lower than that of unsubstituted precatalyst (4d) (k4d-Me = 3.24 ×
10-2 min-1), the catalytic activity of the para-bromo substituted
Scheme 3. Kinetic studies with 4d and 4h.
To explore the turnover-limiting steps in the reaction using
precatalyst (4d), the H/D KIE studies were conducted under
standard conditions using 1-deuterated cinnamaldehyde (5-D)
(>95%-d) (see the Supporting Information). The value of kH/kD
for the precatalyst (4d) was 2.38, which indicates that hydrogen-
transfer from tetrahedral intermediate is at least partially
turnover-limiting in this reaction.
precatalyst (4d-Br) was higher than that of 4d (k4d-Br = 4.51 × 10
−
2 min−1). These results suggest that the length of the alkyl linker
in the N-aryl ortho-substituent contributes to the para-substituent
effect on the catalyst activity.
We next analyzed the proposed kinetic relevance of the
hydrogen-transfer step which generating the conjugated Breslow
intermediate in the homoenolate annulation. The rate constants
of deuterium exchange at the C()-H position in the tetrahedral
intermediate model were assessed by 1H NMR spectroscopy
using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMSO-d6
and 10 vol% D2O (Scheme 4). Deuterium exchange studies
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were carried out with 4a-MOM18 derived from IMes (4a), 4d-
MOM derived from the ether-type precatalyst 4d, and 4h-MOM
derived from the methylene-type precatalyst 4h. In each case,
deuteroxide-catalyzed exchange of C()-H to C()-D could be
monitored without any side reactions and 4d-MOM showed a
higher rate constant than the 4a-MOM and 4h-MOM (kex 4a-MOM =
2.37 × 10-2 min-1, kex 4d-MOM = 4.73 × 10-2 min-1, kex 4h-MOM = 3.74 ×
10-2 min-1) for the deuterium exchange. Even in the absence of
DBU, 5% deuterium exchange was observed with the ether-type
4d-MOM after 12 days, while this exchange was not observed
with 4a-MOM and 4h-MOM. These results suggest that the
oxygen atom in the N-aryl ortho-substituent of 4d-MOM
facilitates the deuterium exchange. We speculated that the
proximity effects of Lewis base functionality could play an
important role in the enhanced rate of deuterium exchange for
4d-MOM.19
Figure 4 shows the 1H NMR analysis of 4d-MOM and 4h-
MOM in CDCl3, This shows that the C() protons of 4d-MOM are
non-equivalent while the C() protons of 4h-MOM are
chemically equivalent. This suggests that the pendant methoxy
groups in 4d-MOM could interact with acidic C() protons,
restricting rotation about the C-C bond. This was supported by
X-ray crystallographic analysis of 4d-MOM.20
Figure 4. 1H NMR spectra (CDCl3, 400 MHz) of (a) 4d-MOM and (b) 4h-MOM.
Next, we sought to investigate the proximity effects of the
alkoxy groups on the formation of tetrahedral intermediates.
Although the detection and isolation of the NHC-aldehyde
adducts derived from aryl aldehydes has been reported,13b, 13c, 21
the adducts derived from enals have not been identified. In
seeking to synthesize the enal-derived adducts, we found that
the combination of -chlorocinnamaldehyde (8) and IMes
delivered the desired adduct (9a) in 3% isolated yield (Scheme
5a).22
Scheme 4. Deuterium exchange study of the tetrahedral intermediate model.
Starting conditions: NHC-MOM (0.005 M), DBU (0.025 M), in DMSO-d6 : D2O =
9:1 at 25 ºC.
Scheme 5. (a) Isolation of IMes-,-enal adduct 9a. (b) Equilibrium
experiments for tetrahedral intermediate. Starting concentration: -
chlorocinnamaldehyde 8 (0.043 M), precatalyst 4 (0.043 M), Et3N (0.043 M) in
CDCl3 at 25 ºC.
With
successful
results
produced
by
-
chlorocinnamaldehyde, we monitored by 1H NMR spectroscopy,
the stoichiometric reactions of each catalyst (4d or 4h) with an
equimolar amount of
8 and Et3N under pre-steady-state
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conditions in CDCl3 (0.043 M) at 25 °C (Scheme 5b). Kinetic
analysis of the reaction profile, which could be monitored without
side reactions, allowed the determination of pseudo-second-
order rate constants (k1, M-1 min-1) and equilibrium constants
(Keq, M-1) for tetrahedral intermediate formation. The pseudo-
first-order rate constants (k-1, min-1) for dissociation of the
tetrahedral intermediate were calculated from Keq = k1/k-1. The
observed rate constant of the forward reaction with the ether-
type precatalyst (4d) was k1 = 4.50 × 10-2 M-1 min-1, half that of
the methylene-type precatalyst (4h) (k1 = 10.1 × 10-2 M-1 min-1),
indicating that the pendant alkoxy groups have a negative effect
on the nucleophilic attack of NHCs to enals. This is probably due
to the electronic repulsion between oxygen atoms in the N-aryl
groups and the chlorine atom of 8. Interestingly, the dissociation
constant k-1 of 4d was also lower than that of 4h. This lower
dissociation constant of 4d can be attributed to the proximity
effects of pendant alkoxy groups on the NHC-enal adducts,
which can impede the dissociation process, even with the similar
electronic repulsion. Even though the equilibrium constant of 4d
is smaller than that of 4h, 4d shows the higher catalytic activity
(Scheme 3). Thus, we concluded that the pendant alkoxy group
contributes mainly to the formation of the conjugated Breslow
intermediate rather than to the formation of the tetrahedral
intermediate.
increasing the NHC catalyst activity where the hydrogen-transfer
of the tetrahedral intermediate is the turnover-limiting step.
To confirm the utility of the catalyst design, we conducted
reaction competition studies using the precatalysts 4d and 4h of
well-known NHC-catalyzed reactions proceeding via a Breslow
intermediate or a conjugated Breslow intermediate (Scheme 6).
In all cases, the reaction conditions screened were identical and
with the exception of the catalyst structure, no attempts was
made to optimize the reaction conditions. The precatalyst 4d
gave a higher yield than precatalyst 4h for the cyclopentene
formation via homoenolate addition (Scheme 6a).5 On the other
hand, the formation of -lactam4 was slightly favored with
precatalyst 4h over 4d (Scheme 6b). This can presumably be
attributed to the protonation of pendant alkoxy groups in the
protic solvent which suppresses the proximity effects. Similarity,
comparison of precatalysts 4d and 4h, shows that the reactivity
of precatalyst 4d was higher than that of precatalyst 4h in terms
of the chemical yields of benzoin condensation via an acyl anion
equivalent,23 esterification with an oxidant24 or dihydropyranone
Scheme 6. Reaction competition studies using precatalyst 4d and 4h.
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from The Ministry of Education,
Culture, Sports, Science and Technology, Japan. R.K. is grateful
for the Amano Institute of Technology scholarship. We are
grateful to Dr. Hiroyasu Sato (Rigaku) for the assistance in X-ray
crystal analysis.
formation via
a
conjugated acyl azolium intermediate25
(Schemes 6c-6e). These results suggest that the precatalyst 4d
with pendant alkoxy groups is effective not only in -
butyrolactone formation but also in various NHC-catalyzed
reactions.
In conclusion, we have successfully identified novel NHC
catalysts suitable for homoenolate annulation of ,-unsaturated
aldehydes and arylaldehydes by the functionalization of N-aryl
substituents facilitating the generation of the conjugated Breslow
intermediate. The key to this success is the installation of the
oxygen atoms at the appropriate position of N-aryl substituents.
Comparative studies and structural analyses indicated that
pendant alkoxy groups are involved in the hydrogen-transfer
step, thereby accelerating the formation of the conjugated
Breslow intermediate from the catalytically generated tetrahedral
intermediate. Since the utility of this catalyst can also be found in
a wide range of NHC-catalyzed reactions which proceed via
Breslow intermediates, these studies provide a new approach to
Conflict of interest
The authors declare no conflict of interest.
Keywords: N-heterocyclic carbenes • organocatalysis •
annulation • kinetic study • umpolung
[1]
For selected recent reviews on NHC catalysis, see: a) D. Enders, O.
Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606; b) J.
Mahatthananchai, J. W. Bode, Acc. Chem. Res. 2014, 47, 696; c) M. N.
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Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510, 485;
d) D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis, Chem.
Rev. 2015, 115, 9307; e) R. S. Menon, A. T. Biju, V. Nair, Beilstein J.
Org. Chem. 2016, 12, 444; f) M. H. Wang, K. A. Scheidt, Angew. Chem.
Int. Ed. 2016, 55, 14912; Angew. Chem. 2016, 128, 15134; g) C. Zhang,
J. F. Hooper, D. W. Lupton, ACS Catal. 2017, 7, 2583; h) Y. Wang, D.
Wei, W. Zhang, ChemCatChem 2018, 10, 338; i) X.-Y. Chen, Q. Liu, P.
Chauhan, D. Enders, Angew. Chem. Int. Ed. 2018, 57, 3862; Angew.
Chem. 2018, 130, 3924.
Cheng, J. Org. Chem. 2017, 82, 9675; d) Y. Niu, N. Wang, A. Muꢁoz, J.
Xu, H. Zeng, T. Rovis, J. K. Lee, J. Am. Chem. Soc. 2017, 139, 14917;
e) Z. Wang, F. Wang, X.-S. Xue, P. Ji, Org. Lett. 2018, 20, 6041.
[12] a) T. Rovis, Chem. Lett. 2008, 37, 2; b) J. Mahatthananchai, J. W. Bode,
Chem. Sci. 2012, 3, 192.
[13] a) J. L. Moore, A. P. Silvestri, J. R. de Alaniz, D. A. DiRocco, T. Rovis,
Org. Lett. 2011, 13, 1742; b) C. J. Collett, R. S. Massey, O. R. Maguire,
A. S. Batsanov, A. C. O’Donoghue, A. D. Smith, Chem. Sci. 2013, 4,
1514; c) C. J. Collett, R. S. Massey, J. E. Taylor, O. R. Maguire, A. C.
O’Donoghue, A. D. Smith, Angew. Chem. Int. Ed. 2015, 54, 6887;
Angew. Chem. 2015, 127, 6991; d) A. Levens, F. An, M. Breugst, H.
Mayr, D. W. Lupton, Org. Lett. 2016, 18, 3566.
[2]
[3]
a) C. Burstein, F. Glorius, Angew. Chem. Int. Ed. 2004, 43, 6205;
Angew. Chem. 2004, 116, 6331; b) S. S. Sohn, E. L. Rosen, J. W.
Bode, J. Am. Chem. Soc. 2004, 126, 14370.
P.-C. Chiang, M. Rommel, J. W. Bode, J. Am. Chem. Soc. 2009, 131,
8714.
[14] L. Hintermann, Beilstein J. Org. Chem. 2007, 3, No. 22.
[15] J. H. Kim, K. A. Jo, Y. S. Son, S. R. Park, K.-H. Ahn, E. J. Kang, Bull.
Korean Chem. Soc. 2009, 30, 2464.
[4]
[5]
M. He, J. W. Bode, Org. Lett. 2005, 7, 3131.
V. Nair, S. Vellalath, M. Poonoth, E. Suresh, J. Am. Chem. Soc. 2006,
128, 8736.
[16] We speculate that a significant positive intercept with precatalyst (4e)
reflects a complex system of very early stages of the reaction.
[17] See the Supporting Information for the details.
[6]
[7]
[8]
[9]
V. Nair, M. Poonoth, S. Vellalath, E. Suresh, R. Thirumala, J. Org.
Chem. 2006, 71, 8964.
[18] A. Berkessel, S. Elfert, V. R. Yatham, J.-M. Neudörfl, N. E. Schlörer,
Angew. Chem. Int. Ed. 2012, 51, 12370; Angew. Chem. 2012, 124,
12537.
J. Liu, D. K. Das, G. Zhang, S. Yang, H. Zhang, X. Fang, Org. Lett.
2018, 20, 64.
a) S. Urban, M. Tursky, R. Frꢀhlich, F. Glorius, Dalton Trans. 2009,
6934; b) J. Kaeobamrung, J. W. Bode, Org. Lett. 2009, 11, 677.
R. Kyan, K. Sato, N. Mase, N. Watanabe, T. Narumi, Org. Lett. 2017,
19, 2750. The value is lower than that of IMesCl (kIMes = 3.57 × 10−2
min−1)9 from ref 9 probably due to the different reaction conditions.
[19] Another possible explanation is that the inductive effects of the pendant
methoxy groups that would increase the acidity of C()-H of the
intermediate.
[20] See the Supporting Information for the details.
[21] T. E. Reynolds, C. A. Stern, K. A. Scheidt, Org. Lett. 2007, 9, 2581.
[22] See the Supporting Information for details of structural analysis.
[23] D. Enders, U. Kallfass, Angew. Chem. Int. Ed. 2002, 41, 1743; Angew.
Chem. 2002, 114, 1822.
[10] V. R. Yatham, J.-M. Neudörfl, N. E. Schlörer, A. Berkessel, Chem. Sci.
2015, 6, 3706.
[11] a) E. M. Higgins, J. A. Sherwood, A. G. Lindsay, J. Armstrong, R. S.
Massey, R. W. Alder, A. C. O’Donoghue, Chem. Commun. 2011, 47,
1559; b) R. S. Massey, C. J. Collet, A. G. Lindsay, A. D. Smith, A. C.
O’Donoghue, J. Am. Chem. Soc. 2012, 149, 20421; c) Z. Li, X. Li, J.-P.
[24] S. De Sarkar, S. Grimme, A. Studer, J. Am. Chem. Soc. 2010, 132,
1190.
[25] F.-G. Sun, L.-H. Sun, S. Ye, Adv. Synth. Catal. 2011, 353, 3134.
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10.1002/anie.202008631
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
R. Kyan, K. Sato, N. Mase, T. Narumi*
Page No. – Page No.
Pendant Alkoxy Groups on N-Aryl
Substitutions Drive the Efficiency of
Imidazolylidene
Catalysts
for
Homoenolate Annulation from Enal
and Aldehyde
The formation of conjugated Breslow intermediate is a turnover-limiting steps in the
NHC-catalyzed -butyrolactone formation via homoenolate addition. Structural and
mechanistic studies including deuterium exchange experiments revealed that the
formation of conjugated Breslow intermediate is facilitated by the proximity effects
of pendant alkoxy groups on ortho-N-aryl groups of imidazolylidene catalyst.
This article is protected by copyright. All rights reserved.